Abstract Appropriate regulation of host immunity by commensal bacteria at mucosal tissues, including the ocular surface, can prevent infection and limit disease. Our recent data (St. Leger et al, this conference) suggest that Corynebacterium mastitidis (=C. mast), an ocular commensal, elicits production of protective IL-17 from conjunctival gdT cells. What is not known is whether this relationship, when dysregulated, can lead to pathology and disease. In this study, we used a mouse model of Muckle-Wells Syndrome (MWS), which is a human autoinflammatory disease that results in spontaneous inflammation of the conjunctiva, skin and joints. This is caused by a mutation in the NLRP3 gene (cias1) that leads to an overactive NLRP3 inflammasome and results in production of multiple proinflammatory cytokines, including, most prominently, IL-1b. Here, we show that ocular colonization with a commensal bacterium, C. mast, induces ocular inflammation in MWS mice, but not in WT controls. Dendritic cells from MWS mice produced increased amounts of IL-1b upon stimulation with C. mast lysates. In keeping with this, DCs harvested from MWS mice more efficiently activated gdT cells (in particular, Vγ4+ cells) in co-culture experiments, compared to DCs from WT mice. Our results suggest that the commensal C. mast can act as a pathobiont and trigger ocular inflammation in mice with an overactive NLRP3 inflammasome. Thus, an aberrant immune response to commensal microbes in humans with this mutation may be the cause of recurrent conjunctivitis in patients with MWS or similar autoinflammatory diseases.